A 5-year, 6-site study, consisting of 6 interlocking R01 applications is proposed to study the treatment of SSRI-resistant depression in 400 adolescents. Subjects will be those with DSM-IV MDD, currently in treatment, and still depressed despite at least 6 weeks of treatment, at least 2 weeks of which are at a higher dosage (40mg) of either paroxetine or fluoxetine and the remainder at an adequate dosage (20 mg). We focus on these two SSRIs because they are most commonly used drugs in this class, and the only two for which efficacy has been demonstrated for the treatment of adolescent depression. After an initial assessment, the adolescents will be observed at the higher dosage of SSRI for an additional 2 weeks and then be reassessed. Those who show no significant response over that time (decrease in CDRS-R equal to or <20%) will be tapered from their current regimen and entered into the protocol. These 400 subjects will be assigned to one of four conditions to be delivered over 12 weeks. The rate of clinically acceptable response to treatment (defined as a CGI-I equal to or <2 and equal to or >50% decrease in the CDRS-R) will be compared across the 4 cells in a 2x2 factorial design: (l) switch within SSRI class (those On paroxetine switch to fluoxetine; those on fluoxetine switch to paroxetine); (2) switch to a different class of agent (venlafaxine); (3) switch within SSRI class plus receive cognitive behavior therapy (CBT), and; (4) switch to a different class of agent (venlafaxine) plus CBT. Subjects who show a clinically acceptable response will receive l2 additional weeks of continuation treatment with the same intervention as in the acute phase. Non- responders will be offered 12 weeks of open treatment. All subjects will be followed up for l2 months after the continuation phase, regardless of treatment compliance. We hypothesize that there will be a medication effect (venlafaxine superior to SSRI switch), a CBT effect (CBT + medication superior to medication alone), and that CBT + venlafaxine superior to the other 3 cells. In addition, we hypothesize that the rate of relapse and recurrence will be lower in the CBT treated cells. The six sites participating and the number of subjects to be enrolled are: Brown (n=40), the site of this application, Dallas (n=80), Galveston (n=80), Oregon (n=80), UCLA (n=40), and Pittsburgh (n=80), with the latter being the coordinating site for the overall study.